Antepartum Dental Radiography and Infant Low Birth WeightFREE

Author Affiliations: Department of Dental Public Health Sciences (Drs Hujoel and del Aguila), Department of Orthodontics (Dr Bollen), School of Dentistry, Department of Epidemiology, School of Public Health (Dr Hujoel), and General Internal Medicine, School of Medicine (Ms Noonan), University of Washington; and Washington Dental Service (Dr del Aguila), Seattle.

ABSTRACT

Context Both high- and low-dose radiation exposures in women have been associated
with low-birth-weight offspring. It is unclear if radiation affects the hypothalamus-pituitary-thyroid
axis and thereby indirectly birth weight, or if the radiation directly affects
the reproductive organs.

Participants and Setting Enrollees of a dental insurance plan with live singleton births in Washington
State between January 1993 and December 2000. Cases were 1117 women with low-birth-weight
infants (<2500 g), of whom 336 were term low-birth-weight infants (1501-2499
g and gestation ≥37 weeks). Four control pregnancies resulting in normal-birth-weight
infants (≥2500 g) were randomly selected for each case (n = 4468).

Main Outcome Measures Odds of low birth weight and term low birth weight by dental radiographic
dose during gestation.

Results An exposure higher than 0.4 milligray (mGy) during gestation occurred
in 21 (1.9%) mothers of low-birth-weight infants and, when compared with women
who had no known dental radiography, was associated with an adjusted odds
ratio (OR) for a low-birth-weight infant of 2.27 (95% confidence interval
[CI], 1.11-4.66, P = .03). Exposure higher than 0.4
mGy occurred in 10 (3%) term low-birth-weight pregnancies and was associated
with an adjusted OR for a term low-birth-weight infant of 3.61 (95% CI, 1.46-8.92, P = .005).

Prepubertal, adolescent, and pregnant females exposed to ionizing radiation
may be at an increased risk for delivering a low-birth-weight (LBW) infant
(<2500 g). In prepubertal girls, high-dose therapeutic radiation for childhood
cancers has been associated with an increased risk for future LBW offspring,
and a direct relationship has been reported between the radiation dose and
LBW risk.1- 3 In
adolescents, diagnostic radiation for idiopathic scoliosis was also associated
with a dose-dependent increased LBW risk.4 In
pregnant women, medical x-ray radiation, not dental x-ray radiation, has been
associated with an increased LBW risk,5 and
exposure to the atomic bomb explosion in Hiroshima during early pregnancy
has been associated with offspring of small stature and head circumference.6 These latter effects occurred at very low doses, the
lowest yet known to produce grossly detectable effects in the offspring of
exposed mothers.6

It is currently unclear whether radiation affects the reproductive organs
directly, or thyroid function and thereby indirectly pregnancy outcomes, or
whether factors unrelated to radiation are responsible for the LBW.7 Because dental diagnostic radiography results in measurable
radiation doses to the hypothalamus-pituitary-thyroid axis8 and
not the reproductive organs or the fetus,9 it
provides an opportunity to test the role of the hypothalamus-pituitary-thyroid
axis in the radiation-LBW association. The goal of this study was to evaluate
whether dental radiography influences the likelihood for a LBW infant in a
population-based case-control study.

METHODS

Identification of Cases and Controls

We conducted a population-based case-control study linking dental utilization
data from Washington Dental Service (WDS), a not-for-profit dental insurance
company, and vital record birth certificates from Washington State. All women
between the ages of 12 and 45 years, with a dental treatment between January
1, 1993, and December 31, 2000, were identified, and a client file was created
that contained the first and last name, address, city, zip code, and birth
date. This file was sent to the birth certificate data manager (with no affiliation
to WDS) who created a unique identifier for each record and linked the data
to the vital record birth certificates using both deterministic and probabilistic
matching procedures. Only singleton births were included.

The combination of the mother's exact birth date along with the mother's
first name and either the father's last name or mother's maiden name gave
a conclusive match for 94.1% of the matched sample of women. Exact date of
mother's birth, along with a partial name match (first 5 characters of last
name and first character of first name) accounted for a further 2.7% of matches.
Partial name matches (first 7 characters of last name and first 5 characters
of first name) and either an address match (0.5%) or transposed date of mother's
birth year, month, or day segment (2.7%) accounted for the remaining matches.

During this matching process, the WDS data manager only received infant
birth dates from the birth certificate data manager, and the birth certificate
data manager did not receive dental utilization data from WDS. All successful
matches combined with infant birth dates (n = 29 215) were sent back
to WDS where it was determined whether eligibility for dental services existed
during a period 40 weeks prior to birth and for how many months eligibility
existed. Prior to 1995, eligibility for dental services could only be determined
for those women who had at least 1 dental visit, whereas subsequent to 1995,
eligibility could be determined regardless of whether a dental visit occurred.
This change in method of determining eligibility did not affect the reported
findings.

The unique identifiers of those women eligible for dental services during
pregnancy were sent to the birth certificate data manager who then selected
the case-control study population. The case group consisted of all pregnancies
resulting in LBW infants. Four normal-birth-weight (NBW) infants (2500 g-5414
g) were randomly selected for each case without matching. Each NBW infant
had an associated random number, which was generated using the "ranuni" function
in SAS, version 8.2 (SAS Institute Inc, Cary, NC). The 4468 infants with the
lowest random numbers were included in the sample. Both the WDS and birth
certificate data managers subsequently stripped their respective data files
of personal identifiers and sent them to the University of Washington where
linking occurred using the patient unique identifier. Human subject approval
was obtained from the Human Research Review Board of the Department of Health
in the State of Washington.

Low birth weight was defined as any infant weighing less than 2500 g.
Low-birth-weight infants were subdivided into 3 categories: very low-birth-weight
(VLBW) infants (≤1500 g), preterm low-birth-weight (PLBW) infants (between
1501-2499 g and <37 weeks' gestation), and term low-birth-weight (TLBW)
infants (1501-2499 g and ≥37 weeks' gestation). Sixteen infants with a
birth weight between 1501 and 2499 g and of unknown gestational age could
not be classified.

Dental Radiography Doses

Dental radiography can affect at least 3 organs in the head-and-neck
region that are potentially involved in pregnancy outcomes: the hypothalamus,
the pituitary, and the thyroid. Because of the evidence on thyroid susceptibility
to radiation,10 and because of the existing
hypothesis that radiation-induced thyroid dysfunction causes LBW,7 radiation doses to the thyroid were calculated. For
each woman, the date and type of each dental radiograph taken was abstracted
from the dental utilization data, doses were assigned to each type of radiographic
exposure, and summed. Doses were estimated based on a nationwide 1993 dental
survey evaluation of x-ray trends11 and published
thyroid radiation doses.12 Given that mean
skin exposure of a dental radiograph is typically 2.17 milligray (mGy),11 that 90% of the sampled dental offices use D-speed
film,13 and that the mean kilovoltage in dental
offices is approximately 70,13 a full-mouth
dental survey consisting of 21 radiographs can be expected to result in a
typical dose to the thyroid of an adult female of 1.6 mGy.8 The
dose to the thyroid of a periapical dental radiograph, while dependent on
the positioning of the x-ray unit, will on average equal 0.08 mGy. In a female
patient, 4 bitewings is 14% of the total radiation dose of a full-mouth radiograph
or 0.22 mGy.12 A cephalometric radiograph was
estimated as delivering a dose of 0.46 mGy to the thyroid14 and
a panoramic radiograph, 0.12 mGy.15 Both are
estimates to the central thyroid region. Doses to the left and right lobe
of the thyroid can be substantially higher. We did not have information on
thyroid shield use, but its use for intraoral films is reported to be low
(Mike Odlaug, MPH, written communication, December 2003). The calculated cumulative
radiation doses during gestation were categorized into 3 dose groups: 0 mGy
(no known dental radiography), 0.1-0.4 mGy, and higher than 0.4 mGy. The value
of 0.4 mGy corresponded to the 90th percentile of cumulative radiation doses
among women with at least 1 dental x-ray. Radiation doses were also modeled
as a continuous variable.

The WDS electronic database is validated both at treatment planning
and completion phases by conducting random or data-driven patient record audits.16 In addition, a recently concluded validation study
indicated that the proportion agreement between chart audits and electronic
records averaged almost 97% for all dental procedures and 93% for radiographic
dental procedures.16 For all analyses, the
radiation dose since the last menstrual period prior to pregnancy was calculated.
For 109 women (1.9%), the gestational length was not recorded, and an estimate
of 40 weeks of gestational length was used. Sensitivity analyses indicated
that the inclusion or exclusion of these 109 women did not affect the findings.

Confounding Variables

Both the birth certificate records and the dental utilization data provided
information on the following variables: maternal age at the time of delivery
(categorized into <20, 20-24, 25-29, 30-34, 35-39, ≥40 years), ethnicity
(17 categories were condensed into white, black, Asian, and other ethnicities—the
latter group included women of unknown ethnicity and women who refused to
state ethnicity), education level of mother (unknown, ≤12 years of education,
>12 years of education), the duration of eligibility for dental insurance
during pregnancy, dental procedures during pregnancy, marital status, parity
(categorized into 0, 1-2, and ≥3 prior pregnancies), self-reported maternal
smoking during pregnancy, the presence of gestational or established diabetes,
the Kessner Adequacy of Prenatal Care Index,17 self-reported
consumption of 1 or more alcoholic drinks per week during pregnancy, prepregnancy
weight, weight gain during pregnancy, preeclampsia, and chronic hypertension.

Statistical Analysis

Between 1993 and 2000, the 5719 women in the selected study sample had
1 singleton birth, 197 women had 2 singleton births, and 4 women had 3 singleton
births. To take into account that the pregnancy outcomes for women with more
than 1 birth are correlated events, generalized estimating equation models
were used. Odds ratios (ORs) were calculated using generalized linear models
with an exchangeable correlation structure, a logit link, and a binomial error
distribution. Case-control differences in potential confounders were estimated
using exchangeable correlation matrices, with the exception of prepregnancy
weight where an independence correlation structure was used. Correlation coefficients
and the respective P values describing the association
between dental radiation and potential confounders were estimated ignoring
within-subject correlation. The statistical significance level was set at
.05.

The impact of missing values was assessed with multiple imputations
of missing values using a sequential regression imputation method (Imputational
and Variance Estimation software [IVEware], version 2.0, University of Michigan,
Ann Arbor).18 This method imputed values for
each woman conditioned on the other values observed for that woman. The imputations
were drawn from the posterior distribution specified by a regression model
with a noninformative prior distribution. Values were imputed cyclically,
each time overwriting previously drawn values. Subsequently, regression models
were built using the jackknife repeated replication technique.

RESULTS

There were 1117 LBW infants born to women with WDS insurance between
1993 and 2000: 193 VLBW infants, 572 PLBW infants, 336 TLBW infants, and 16
of unknown gestational age (Table 1).
A total of 4468 NBW controls were selected. The LBW rate among women with
private dental insurance was 3.8%, or 0.7% lower than the LBW rate (4.5%)
for Washington State during the same period (1993-2000). When compared with
all women who had live births in Washington State, women who had private dental
insurance were on average 1.5 years older (28.8 vs 27.3 years), more educated
(14.3 years vs 12.9 years), smoked less (7.5% vs 14.6%), and were more likely
to be white (81% vs 73%).

Dental radiation exposures were more common among women with LBW infants
than among women with NBW infants. Among the women who delivered a LBW infant,
1.9% (n = 21) had higher than 0.4 mGy radiation, as opposed to 1.0% of the
women with NBW infants (P = .02) (Table 2). Among the women who delivered a TLBW infant, the prevalence
of the higher than 0.4 mGy radiation dose was 3.0% (n = 10), which was also
significantly higher than among controls (P = .002).
The prevalence of the higher than 0.4 mGy radiation dose among women with
a PLBW infant and a VLBW infant was 1.6% and 1.0%, respectively, which was
not significantly different from the prevalence in women with NBW infants
(P = .24 and P>.99, respectively).
Established risk factors for LBW such as maternal age, diabetes, smoking,
ethnicity, preeclampsia, chronic hypertension, prepregnancy weight, maternal
weight gain, and parity were significantly associated with LBW in the studied
population (Table 1).

When compared with women with no known dental diagnostic radiography,
a thyroid radiation dose of more than 0.4 mGy increased the adjusted odds
for LBW by 2.27 (95% confidence interval [CI], 1.11-4.66) (Table 3). A thyroid radiation dose of 0.1 to 0.4 mGy was associated
with an adjusted OR of 1.20 (95% CI, 0.88-1.63). When radiation dose was modeled
as a continuous variable, a 1-mGy increase was associated with a 1.83 increased
odds for a LBW infant (95% CI, 1.10-3.04). Further adjustment of the OR for
the different types of dental procedures performed during pregnancy did not
affect the radiation-LBW association (Table
3).

Subsequently, the association between diagnostic radiation and different
types of LBW outcomes was evaluated. There was no significant association
between a radiation dose higher than 0.4 mGy and the OR for VLBW infants (OR,
2.19; 95% CI, 0.21-22.49) or the OR for PLBW infant (OR, 1.77; 95% CI, 0.65-4.78).

There was a strong association between diagnostic radiation and TLBW
infants (Table 3). When the thyroid
radiation dose was higher than 0.4 mGy, the adjusted OR for a TLBW infant
was 3.61 (95% CI, 1.46-8.92) when compared with women with no known dental
radiography. When the radiation dose to the thyroid was 0.1 to 0.4 mGy, the
adjusted OR for a TLBW infant was 1.66 (95% CI, 1.09-2.53). Further adjustment
of the OR for the different types of dental procedures performed during pregnancy
did not affect the OR (Table 3).
When the cumulative radiation dose was modeled as a continuous variable, a
1-mGy increase was associated with a 2.59 increased odds for a TLBW infant
(95% CI, 1.37-4.90) after adjustment for confounding variables. When values
were imputed for missing confounders, the OR for a TLBW infant associated
with a radiation dose to the thyroid higher than 0.4 mGy was 2.89 (95% CI,
1.32-6.33) when compared with women with no known dental radiography.

Subgroup analyses showed strong associations among women with adequate
prenatal care or women reporting not smoking. Thyroid radiation higher than
0.4 mGy in nonsmokers was strongly associated with TLBW infants (naive OR,
4.81; 95% CI, 1.81-12.79). The naive OR estimate among women reporting smoking
during pregnancy was 1.61 (95% CI, 0.15-17.34). Among women with adequate
prenatal care, thyroid radiation higher than 0.4 mGy was associated with an
OR for a TLBW infant of 4.38 (95% CI, 1.79-10.74) when compared with women
with no known dental radiography.

Over two thirds of the total radiation doses (70.5%) were received in
the first trimester. During the first trimester, a radiation dose higher than
0.4 mGy was associated with an OR for a LBW infant of 3.11 (95% CI, 1.44-6.73)
and the OR for a TLBW infant was 5.49 (95% CI, 2.12 -14.17). During the second
and third trimester, the confidence limits around the OR were too wide to
make meaningful inferences.

COMMENT

In this study, antepartum dental radiography in pregnant women was associated
with an increased risk for a LBW infant, especially a TLBW infant. The prevalence
of dental radiography during pregnancy in this dentally insured population
was approximately 10%. Since women may not always be aware of their pregnancy
status, it may not be possible to eliminate all dental radiography during
pregnancy, but if this goal could be achieved and if the identified association
is causal, the prevalence of TLBW infants could be reduced by up to 5%. Current
guidelines for diagnostic radiography,19 which
are based on the notion that only direct radiation to the reproductive organs
is of concern during pregnancy, may need to be evaluated further.

While the findings of this study cannot determine which organ in the
head-and-neck region may be responsible for the observed radiation-LBW association,
epidemiological20- 22 and
experimental evidence23 point to the thyroid.
Very low-dose radiation has been associated with thyroid dysfunction such
as thyroid autoimmunity among young females, thyroid cysts in females of all
ages,24 and papillary thyroid cancer25 among multiparous women. The thyroid's susceptibility
to radiation has been hypothesized to be high during pregnancy.26 In
addition to the evidence on radiation-induced thyroid dysfunction, there is
evidence that subtle, subclinical thyroid dysfunction decreases birth weight20,21 and delays neurointellectual development
of the offspring.27,28 This raises
the possibility that radiation-induced thyroid dysfunction may also affect
the neurointellectual development of the offspring. Low-dose radiation in
utero leads to poor performance on intelligence tests.29 While
those associations have typically been attributed to the direct effects of
radiation on the development of the brain,29 the
potential role of radiation-induced thyroid dysfunction on brain development
may need to be further explored.

Strengths of this study include the unbiased selection of cases and
controls from registries, the individual radiation dosimetry data, the absence
of recall bias with respect to radiation between cases and controls, the control
for well-established risk factors of LBW, and the validation of the insurance
records with respect to dental radiography information. Such rigor in design
has often been difficult to achieve when studying the effects of radiation
on pregnancy outcomes. In prior studies, birth weight was often assessed by
maternal recall, selection bias was difficult to control due to nonresponse
or survival bias, and bias due to confounding from the lack of information
on other risk factors for LBW, such as diabetes, chronic hypertension, or
smoking,1,3- 5,7 could
not always be adjusted for.

Several factors reduced the potential for residual confounding. First,
because all women had private dental insurance, the selected sample was of
a higher and more homogeneous socioeconomic class (eg, higher education) and
had better health awareness (eg, lower smoking prevalence) than the population
of Washington State. Such restriction in subject selection is a useful tool
to control confounding.30 However, such restriction
had the disadvantage that it limited the ability to assess effect modification—the
number of women in certain subgroups, such as women reporting smoking or women
with inadequate prenatal care, was too sparse to provide meaningful inferences.
Second, dental radiography doses were not related to important risk factors
of LBW such as maternal age, diabetes, preeclampsia, and chronic hypertension.
Third, among women exposed during the first trimester, when radiation has
been reported to have the greatest effect on infant growth,6 the
OR for TLBW was 5 and the lower limit of the 95% CI excluded 2. Odds ratios
of such size are less likely to be the result of residual confounding.31

Weaknesses of the study include potential measurement errors of confounders
such as smoking, the lack of thyroid function measures, the lack of information
on nondental radiation exposures, bias in the linking process, the possibility
of a chance finding, and missing data. It is possible that underreporting
of the socially undesirable behavior of smoking during pregnancy biased the
association between dental radiography and LBW. It is unclear to what extent
restricting the analyses to women reporting not smoking minimized bias since
attendants may be more likely to note smoking on a birth certificate for a
LBW infant than for a NBW infant.32 Some control
for smoking was obtained by restricting the study population to those women
of higher socioeconomic class in whom smoking prevalence is lower. The lack
of thyroid function measures in the current study eliminated our ability to
determine if indeed the thyroid is involved in explaining the observed association.

The likelihood of matching mothers' names may have depended on ethnicity,
which may have induced selection biases because ethnicity was related to both
radiation dose and birth weight. This bias may have been minimized, but not
eliminated, by controlling for ethnicity and ethnicity-related risk factors
for LBW, such as diabetes. The reported results may be a chance finding, but
this is less likely given that prior studies also identified associations
between diagnostic radiation and LBW.4,5 The
prevalence of missing data for certain confounders was moderately high. Even
though imputation for missing values did not substantially influence the results,
it is possible that the missing data biased the results.

The impact of nondental radiation or factors associated with dental
radiography on the reported study findings is unknown. Additional analyses
of data from a population-based case-control study on dental radiation33 suggested that nondental therapeutic or diagnostic
radiation during pregnancy is of low prevalence. It is possible that extensive
dental radiography is associated with certain conditions such as facial trauma,
tumors, or dental diseases, which in this study may have increased the risk
for adverse pregnancy outcomes and caused a spurious association between radiation
and LBW. Since adjustment for treatments of dental diseases did not affect
the ORs, the possibility for dental diseases or treatments to confound the
association is diminished but not eliminated. Furthermore, the observation
that both orthodontic and endodontic therapies, 2 procedures where diagnostic
radiation is common, were associated with TLBW is more suggestive of dental
radiography being associated with LBW than dental diseases or procedures.

In summary, this study provides evidence that very low-dose radiation
to the maternal head-and-neck region during pregnancy is associated with LBW
offspring. If indeed the hypothalamus-pituitary-thyroid axis is somehow involved
in the causal pathway, it is possible that a further understanding of disease
mechanisms may lead to new intervention strategies for those circumstances
where avoidance of very low-dose radiation is difficult. The notion that very
low-dose radiation exposures to nonreproductive organs in expectant mothers
are safe needs to be investigated further.19

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